RXR-ALPHA REGULATES CARDIAC NEURAL CREST CELL MIGRATION

RXR-ALPHA 调节心脏神经嵴细胞迁移

• 批准号: 6388768
• 负责人: TARA R ST AMAND
• 金额: $ 3.48万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6388768
• 关键词: animal tissue; biomarker; cell differentiation; cell migration; congenital heart disorder; embryo /fetus; fluorescent in situ hybridization; heart; heart cell; heart output disorder; histogenesis; histology; laboratory mouse; mammalian embryology; morphology; mutant; neural crest; neural plate /tube; protein localization; retinoate; retinoid binding proteins

The cardiac neural crest cells are necessary for proper heart formation and maturation of individual cardiac chambers. In particular, these cells are involved in the formation of the outflow tract and aortic arch arteries. Requirements for these cells has been best demonstrated by neural crest ablation studies in the chick which results in a variety of cardiac malformations including PTA, VSD, and DORV. Interestingly, these defects resemble various forms of congenital heart disease seen in the clinical setting. In addition, both an excess of retinoic acid (RA) or vitamin A- deficiency leads to similar phenotypes suggesting that RA may also be involved in cardiac neural crest migration and/or differentiation. Furthermore, it has been shown that mutations to the RA receptor RXRalpha lead to similar cardiac phenotypes suggesting that RA signaling pathways regulating the cardiac neural crest cell lineage are mediated via RXRalpha. Therefore the hypothesis under investigation states that outflow tract defects detected in the RXRalpha mutant result from defects in cardiac neural crest cell migration. Two specific aims have been designed to test this hypothesis. (1) To determine if the outflow tract defects found in the RXRalpha deficient embryos is the result of defects in cardiac neural crest cell migration by (a) molecular marker analysis and (b) indicator mouse lines; (2) To determine if the defect in neural crest cell migration is cell autonomous or non-cell-autonomous by (a) co-localization of RXRalpha to the cardiac neural crest cells, (b) neural tube explant cultured and (c) analyzing cardiac neural crest cell migration and outflow tract defects in mice harboring a cardiac neural crest restricted deficiency in RXRalpha.

心脏神经嵴细胞对于心脏的正常形成和单个心腔的成熟是必需的。特别是，这些细胞参与流出道和主动脉弓动脉的形成。对这些细胞的需求已通过鸡的神经嵴消融研究得到最好的证明，该研究导致各种心脏畸形，包括PTA、VSD和DORV。有趣的是，这些缺陷类似于临床上看到的各种形式的先天性心脏病。此外，过量的视黄酸（RA）或维生素A缺乏导致相似的表型，表明RA也可能参与心脏神经嵴迁移和/或分化。此外，已显示RA受体RXR α的突变导致相似的心脏表型，表明调节心脏神经嵴细胞谱系的RA信号传导途径是通过RXR α介导的。因此，正在研究的假设表明，在RXR α突变体中检测到的流出道缺陷是由心脏神经嵴细胞迁移缺陷引起的。为了检验这一假设，设计了两个具体目标。(1)通过（a）分子标记物分析和（B）指示小鼠系确定在RXR α缺陷胚胎中发现的流出道缺陷是否是心脏神经嵴细胞迁移缺陷的结果;（2）通过（a）RXR α共定位于心脏神经嵴细胞，（B）培养的神经管外植体和（c）分析具有心脏神经嵴限制性RXR α缺陷的小鼠的心脏神经嵴细胞迁移和流出道缺陷。